US-France Cooperative Research: Conformation and Dynamics of Nucleic Acids

该奖项将支持阿拉巴马大学伯明翰分校的斯蒂芬·哈维博士和法国巴黎生物物理研究所的理查德·拉弗里博士之间的合作研究。该项目的目标是根据其一级碱基序列来研究核酸的双螺旋结构。由拉弗里博士及其合作者开发的Jumna(核酸连接建模)程序将用于对各种DNA结构进行建模。该程序还将进行修改，将其从结构优化算法转换为分子动力学算法。关于DNA结构，将调查两类问题。首先，将研究DNA序列和双螺旋局部结构变化之间的关系，目的是了解(1)DNA弯曲的起源和(2)蛋白质如何通过结构上的细微变化识别DNA序列。其次，将为与多嘌呤-多嘧啶序列以及与复制和转录相关的结构建立模型。在模型结构元素中将包括茎环结构、单股、包含两股、三股和四股的螺旋以及这些不同元素之间的连接。这些研究将具有重要意义，不仅因为它们提供了对DNA结构的洞察，而且因为所开发的方法将有助于检查DNA和RNA的其他建模问题。根据从这些研究中获得的经验，研究人员将转向将Jumna转化为对核酸进行分子动力学模拟的算法的问题。后一个项目如果成功，将允许在比目前的分子动力学算法可能的更大的系统和更长的时间尺度上进行模拟。哈维博士和拉弗里博士领导的研究小组在核酸模拟领域做出了重要贡献。与蛋白质相比，Nas在模拟方法方面的进展要慢得多。这两个小组所做的工作是独特的和重要的贡献。预计拟议的合作将加快这一领域的进展。

This award will support collaborative research between Dr. Stephen Harvey, University of Alabama at Birmingham, and Dr. Richard Lavery, Institut de Biologie Physico-Chimique, Paris, France. The objective of the project is to study the nucleic acid double helix structure in terms of its primary base sequence. JUMNA (Junction Modeling of Nucleic Acids), a program developed by Dr. Lavery and his collaborators, is to be used to model various DNA structures. The program will also be modified to convert it from a structure optimization algorithm to a molecular dynamics algorithm. With regard to DNA structure, two classes of problems will be investigated. First, the relationship between DNA sequence and the variations in the local structure of the double helix will be examined, with the goal of understanding (1) the origins of DNA bending and (2) how proteins might recognize DNA sequences through subtle changes in structure. Second, models will be built for structures associated with polypurine-polypyrimidine sequences and with replication and transcription. Among the model structural elements will be stem-loop structures, single strands, helices containing two, three, and four strands, and the junctions between these various elements. These studies will be significant not only for the insights they provide into DNA structure, but because the methods developed will be useful for examining other modeling problems for both DNAs and RNAs. With the experience gained from these studies, the investigators will then turn to the problem of converting JUMNA into an algorithm for molecular dynamics simulations on nucleic acids. This latter project, if successful, would allow simulations to be performed on much larger systems and over much longer time scales than is possible with current molecular dynamics algorithms. The research groups headed by both Dr. Harvey and Dr. Lavery have made important contributions in the area of simulation of nucleic acids. Progress in simulation methods has been much slower for NAs than for proteins. The work done by these two groups is unique and an important contribution. The proposed collaboration is expected to accelerate progress in this field.